PEDIATRIC FOIE GRAS: New insights into NAFLD and NASH - - PDF document

4/18/2013 1

PEDIATRIC FOIE GRAS: NON-ALCOHOLIC FATTY LIVER DISEASE

Patrika Montricul Tsai, MD, MPH Pediatric Gastroenterology, Hepatology, and Nutrition University of California, San Francisco May 17, 2013

Updates on…

• New insights into NAFLD and NASH pathophysiology
• New AASLD/AGA/ACG guidelines for NAFLD and NASH,

as pertains to pediatrics

• Evidence-based recommendations for NASH treatment in

children

Disclosures

• I have nothing to disclose

Is NAFLD really a problem in kids?

• Most common pediatric chronic liver disease in North

America

• 2-9% of all U.S. adolescents
• 20% of U.S. obese adolescents
• Rates in younger children unknown

Definitions:

• NAFLD:
• Hepatic steatosis, by imaging or histology
• DIAGNOSIS OF EXCLUSION: No other causes for

secondary hepatic steatosis

• Includes entire disease spectrum:
• NAFL:
• hepatic steatosis
• WITHOUT hepatocellular injury
• WITHOUT fibrosis
• NASH:
• hepatic steatosis
• + inflammation/ballooning
• +/- fibrosis
• Can progress to cirrhosis, ESLD

NAFLD/NASH Progression

4/18/2013 2 Histology of NASH Pediatric NAFLD: Type 1 vs. Type 2

• Type 1 NAFLD:
• “Adult-type”
• Zone 3 steatosis
• Ballooning
• Perisinusoidal fibrosis
• Type 2 NAFLD:
• ?Unique to children
• Zone 1 steatosis
• No ballooning
• Portal inflammation/fibrosis

Loomba et al. HEPATOLOGY 2009;50:1282-1293

NAFLD Pathogenesis

Mantena SK et al. 2008 Bass NM. Hepatology 2010.

Two-hit hypothesis Lipotoxicity hypothesis

Natural history of NAFLD

• Not well understood
• In adults, NASH associated with:
• Increased overall mortality risk
• Leading cause of death: cardiovascular disease
• Increased liver-mortality rate
• NASH cirrhosis: Increased HCC risk (but lower than

Hep C cirrhosis)

• In children: 1 retrospective single center study
• 66 children
• 5 with serial biopsies, 4 with fibrosis progression

Which of the following groups is protected from NAFLD?

• A) African Americans
• B) Asian Americans
• C) Hispanic Americans
• D) None of the above

Demographic Predictors of NAFLD

• Overweight/obesity
• Adolescents
• Males > Females:
• Estrogen protective?
• Ethnicity:
• Hispanics, Asians AT RISK
• African Americans PROTECTED
• Family history: obesity, insulin resistance/DM, NAFLD

Loomba R et al. Advances in Pediatric NAFLD. Hepatology. 2009; 50(4): 1282–1293.

4/18/2013 3 New NAFLD guidelines: June 2012

Grading of recommendations, evidence

• Strength of Recommendation: factors include evidence

quality, importance to patient outcomes, and cost

1.

STRONG

2.

WEAK

• Quality of Evidence
• High (A): Further research unlikely to change confidence in the

estimate of the clinical effect

• Moderate (B): Further research may change confidence in estimate
• f the clinical effect
• Low (C): Further research very likely to impact confidence on the

estimate of clinical effect

AASLD: NAFLD screening?

• Not recommended in adult primary care clinics or

high-risk specialty clinics (diabetes, obesity) (1, B)

• Not recommended in overweight/obese children:
• “Due to a paucity of evidence, a formal recommendation cannot be

made with regards to screening for NAFLD in overweight and

• bese children despite a recent expert committee recommendation

for biannual screening.” (1, B)

• Not recommended for family members of people with

NAFLD or NASH (1, B)

• 18% of NASH patients have a first degree relative with NASH

AAP Guidelines for NAFLD Screening

• Starting at 10 years of age, every 2 years
• AST/ALT in pediatric patients with:
• BMI>85th percentile for age/gender WITH risk factors OR
• BMI>95th percentile for age/gender, regardless of risk factors
• Risk factors:
• Family history of obesity-related diseases, including hypertension,

early cardiovascular deaths, and strokes

• Patient history of elevated blood pressure, hyperlipidemia, or

tobacco use.

• Pediatrics. December 2007, pp. S164-S192, S193-S228

What are “normal” LFTS?

• Screening ALT for Elevation in Today’s Youth (SAFETY)
• U.S. children’s hospitals:
• Median ALT (range):
• ALL: 53 (30-90)
• BOYS: 50 (30-70)
• GIRLS: 40 (29-65)
• NHANES: 12-17 yrs w/o liver disease
• 95th percentile ALT:
• BOYS: 25.8 U/L
• GIRLS: 22.1 U/L

Schwimmer JB et al. Gastroenterology 2010.

Initial evaluation

• AST/ALT
• Does NOT correlate well with presence or severity of NASH
• Medication history
• Family history
• Alcohol screen for adolescents

AND Viral hepatitis:

• Hep A total Ab
• Hep B Sag, Cab,

SAb,

• Hep C Ab

4/18/2013 4

Evaluation of incidental hepatic steatosis

• History, clinical exam, LFTs
• Signs/symptoms liver disease and/or abnormal LFTs:
• Suspected NAFLD,  further workup (1, A)
• NO signs/symptoms liver disease AND normal LFTs:
• Assess for metabolic risk factors (obesity, DM,

dyslipidemia) (1, A)

• NO liver biopsy recommended (1, B)

Ultrasound for hepatic steatosis

Bohte AE et al. Radiology 2012; 262 (1): 327-334.

MRI steatosis “color mapping”

Qayyum A et

• al. AJR,

March 2012.

When to biopsy adults for NAFLD?

• “Should be considered in patients with NAFLD who are at

increased risk to have steatohepatitis and advanced fibrosis” (1, B)

• Metabolic syndrome
• NAFLD Fibrosis Score
• “Patients with suspected NAFLD in whom competing

etiologies for hepatic steatosis and co-existing chronic liver diseases cannot be excluded” (1, B)

When to biopsy children for NAFLD?

• AASLD:
• “where the diagnosis of NAFLD is unclear”
• “where there is possibility of multiple diagnoses”
• “before starting potentially hepatotoxic medications”
• “prior to starting pharmacologic therapy for NASH”
• ESPGHAN:
• “no present consensus or evidence base to formulate guidelines”
• “to exclude other treatable disease”
• “in cases of clinically suspected advanced liver disease”
• “before pharmacologic/surgical treatment”
• “as part of a structured intervention protocol or clinical research trial”

Approach to NAFLD workup and biopsy

4/18/2013 5

Which of the following is not an effective treatment for NAFLD?

• A) Weight loss
• B) Exercise
• C) Vitamin E
• D) Metformin

Lifestyle modification to treat NAFLD:

• Weight loss through lifestyle modification:
• 3-5%: reduced hepatic steatosis (1, B)
• 10%: reduced necro-inflammation (1, B)
• Improved steatosis, lobular inflammation, ballooning,

and NAFLD activity score

• Exercise alone, even without weight loss
• Can significantly decrease hepatic steatosis (1, B)
• 2-3 sessions/week, 30-60 minutes, 6-12 weeks
• In children and adults, no evidence to definitively

recommend a specific diet or exercise plan

Pediatric NAFLD

• Treatment:
• Lifestyle modification (2, B)
• Vitamin E:
• TONIC trial (NASH CRN): RCT of Vitamin E vs. metformin
• vs. placebo x 96 weeks
• NO difference between groups in primary outcome:

sustained ALT reduction

• Vitamin E did significantly decrease NAS and improve

NASH resolution

• Recommendation: 800 IU rrr alpha-tocopherol daily for

children with biopsy-proven NASH or borderline NASH (1, B)

Vitamin E in adults:

• Vitamin E: Recommended at 800 IU/day for biopsy-proven,

non-diabetic ADULTS as first line therapy (1, B)

• Anti-oxidant
• Improves steatosis, inflammation, ballooning, NASH resolution
• Does NOT improve fibrosis
• NASH CRN trials (PIVENS, TONIC) suggest that rrr alpha-tocopherol

at 800IU/day helpful

• Recommended daily allowance: 30 IU/day
• 2 previous meta-analyses failed to show histologic benefits
• ?Increases all-cause mortality
• Conflicting data from meta-analyses
• Recent trial of 400 IU/day associated with increased prostate cancer risk
• NOT recommended in NASH + DM, NAFLD w/o liver biopsy, NASH

cirrhosis, cryptogenic cirrhosis, (1, C) NAFLD/NASH with other chronic liver disease co-existing (1, B)

Medications for NAFLD/NASH:

• Metformin: Not recommended (1, A)
• RCT data for both adults and children
• No effect on AST/ALT or liver histology
• No effect regardless of diabetes as co-morbidity
• Rosiglitazone: Not recommended
• Increased risk coronary events
• Less data than for pioglitazone, but does not seem to improve

inflammation or fibrosis (maybe AST/ALT, steatosis?)

• Pioglitazone: Recommended in biopsy-proven, non-

diabetic ADULTS (1, B)

• Meta-analysis (Vernon G et al, 2011):
• Improves steatosis: OR 4.05, 95% CI 2.58-6.35
• Improves inflammation: OR 3.53, 95% CI 2.21-5.64
• Does NOT improve fibrosis: OR 1.40, 95% CI 0.87-2.24
• Causes weight gain

Medications for NAFLD/NASH:

• UDCA: Not recommended (1, B)
• Several small studies, 1 large RCT: no benefit
• Omega-3 fatty acids: Use to treat hypertriglyceridemia in

NASH patients, but not specifically to treat NAFLD/NASH (1, B)

• Large multicenter study ongoing: eicosapentoic acid
• Other studies small, flawed
• Statins: Use to treat dyslipidemia in NAFLD/NASH

patients (1, B), but NOT as specific treatment for NAFLD/NASH (1, B)

4/18/2013 6 Bariatric surgery and NASH:

• NAFLD/NASH not a contraindication (1, A)
• No RCTs evaluate bariatric surgery as a treatment for

NAFLD/NASH

• In cohort studies, availability of histologic outcomes variable, BUT
• 2 meta-analyses:
• Mummadi et al: bariatric surgery improves steatosis,

steatohepatitis, fibrosis

• Cochrane Review: lack of RCT data prevents definitive

assessment of bariatric surgery as NASH treatment

• Safety and utility in NASH cirrhosis not established (1, B)
• No recommendations on specific types of bariatric surgery for

NAFLD/NASH population

CyNCH trial

• Cysteamine bitartrate delayed-release for treatment of

NASH

• Children 8-17 years of age with histologically proven NASH
• Double-blind, placebo-controlled RCT
• 52 weeks of treatment, 24 week post-treatment follow-up
• 6 follow-up visits
• Post-treatment liver biopsy

Charlton MR et al. Gastro 2011: 1249-1253

Liver transplant: 2001-2009 indications Summary

• NAFLD is the most common pediatric chronic liver

disease in North America

• NAFLD can progress to fibrosis and ultimately require

liver transplant

• Initial evaluation consists of AST and ALT
• Further evaluation may include liver biopsy
• Weight loss and exercise even without weight loss reduce

NAFLD

• Vitamin E is recommended for biopsy-proven NASH

References

• Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and

management of nonalcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological

• Association. Hepatology. 2012 Jun;55(6):2005-23.
• Schwimmer JB, Dunn W, Norman GJ, et al. SAFETY study: alanine

aminotransferase cutoff values are set too high for reliable detection

• f pediatric chronic liver disease. Gastroenterology. 2010

Apr;138(4):1357-64.

• Vajro P, Lenta S, Socha P, et al. Diagnosis of nonalcoholic fatty liver

disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr. 2012 May;54(5):700-13.

UCSF Pediatric Gastroenterology, Hepatology, and Nutrition

• Laura Cooke
• Alex Green
• Betsy Haas-Beckert
• Mel Heyman
• Sue Rhee
• Phil Rosenthal
• Susan Stritzel-Diaz
• Patrika Tsai
• Elizabeth Yen